SPIROHEPTANE SALICYLAMIDES AND RELATED COMPOUNDS AS INHIBITORS OF ROCK

(19)

(11)

EP 3 954 681 A1

(12)	EUROPEAN PATENT APPLICATION

(43)	Date of publication:
	16.02.2022 Bulletin 2022/07

(21)	Application number: 21193297.5

(22)	Date of filing: 13.01.2017

(51)

International Patent Classification (IPC):

C07D 401/14^(2006.01)
A61K 31/4427^(2006.01)
C07D 231/18^(2006.01)
C07D 401/12^(2006.01)
C07D 471/04^(2006.01)
C07D 513/04^(2006.01)

A61K 31/437^(2006.01)
C07D 231/12^(2006.01)
C07D 231/54^(2006.01)
C07D 413/12^(2006.01)
C07D 471/12^(2006.01)
C07D 213/64^(2006.01)

(52)	Cooperative Patent Classification (CPC):
	C07D 401/14; C07D 231/12; C07D 231/18; C07D 231/54; C07D 401/12; C07D 413/12; C07D 471/04; C07D 471/12; C07D 213/64; C07D 513/04; A61P 15/10; A61P 9/10; C07D 239/06

(84)	Designated Contracting States:
	AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
	Designated Extension States:
	BA ME
	Designated Validation States:
	MA MD

(30)

Priority:

13.01.2016 US 201662278122 P

(62)	Application number of the earlier application in accordance with Art. 76 EPC:
	17701785.2 / 3402790

(71)	Applicant: Bristol-Myers Squibb Company
	Princeton, NJ 08543 (US)

(72)

Inventors:

SMITH II, Leon M.
Pennington NJ, 08534 (US)
LADZIATA, Vladimir
Pennington NJ, 08534 (US)
DELUCCA, Indawati
Pennington NJ, 08534 (US)
PINTO, Donald, J. P.
Pennington NJ, 08534 (US)
ORWAT, Michael J.
Pennington NJ, 08534 (US)
DILGER, Andrew K.
Pennington NJ, 08534 (US)
PABBISETTY, Kumar Balashanmuga
Pennington NJ, 08534 (US)
YANG, Wu
Pennington NJ, 08534 (US)
SHAW, Scott A.
Pennington NJ, 08534 (US)
GLUNZ, Peter W.
Pennington NJ, 08534 (US)
PANDA, Manoranjan
560099 Bangalore Karnataka (IN)

(74)	Representative: Kling, Edouard
	Swords Laboratories, Ireland Swiss Branch, Steinhausen Hinterbergstrasse 16 6312 Steinhausen 6312 Steinhausen (CH)


	Remarks:
	This application was filed on 26.08.2021 as a divisional application to the application mentioned under INID code 62.

(54)	SPIROHEPTANE SALICYLAMIDES AND RELATED COMPOUNDS AS INHIBITORS OF ROCK

(57) The present invention provides compounds of Formula (I):

or stereoisomers, tautomers, or pharmaceutically-acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective ROCK inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating cardiovascular, smooth muscle, oncologic, neuropathologic, autoimmune, fibrotic, and/or inflammatory disorders using the same.

Description

FIELD OF THE INVENTION

[0001] The present invention relates generally to novel spiroheptane salicylamides and their analogues thereof, which are inhibitors of Rho kinases, compositions containing them, and methods of using them, for example, for the treatment or prophylaxis of disorders associated with aberrant Rho kinase activity.

BACKGROUND OF THE INVENTION

[0002] Rho-Kinase (ROCK) is a member of the serine-threonine protein kinase family. ROCK exists in two isoforms, ROCK1 and ROCK2 (Ishizaki, T. et al., EMBO J., 15:1885-1893 (1996)). ROCK has been identified as an effector molecule of RhoA, a small GTP-binding protein (G protein) that plays a key role in multiple cellular signaling pathways. ROCK and RhoA are ubiquitously expressed across tissues. The RhoA/ROCK signaling pathway is involved in a number of cellular functions, such as ACTIN^® organization, cell adhesion, cell migration, and cytokinesis (Riento, K. et al., Nat. Rev. Mol. Cell Biol., 4:446-456 (2003)). It is also directly involved in regulating smooth muscle contraction (Somlyo, A.P., Nature, 389:908-911 (1997)). Upon activation of its receptor, RhoA is activated, and, in turn, it activates ROCK. Activated ROCK phosphorylates the myosin-binding subunit of myosin light chain phosphatase, which inhibits activity of the phosphatase and leads to contraction. Contraction of the smooth muscle in the vasculature increases blood pressure, leading to hypertension.

[0003] There is considerable evidence in the literature that the Rho A/ROCK signaling pathway plays an important role in signal transduction initiated by several vasoactive factors, for example angiotensin II (Yamakawa, T. et al., Hypertension, 35:313-318 (2000)), urotension II (Sauzeau, V. et al., Circ. Res., 88:1102-1104 (2001)), endothelin-1 (Tangkijvanich, P. et al., Hepatology, 33:74-80 (2001)), serotonin (Shimokawa, H., Jpn. Circ. J., 64:1-12 (2000)), norepinephrine (Martinez, M.C. et al., Am. J. Physiol., 279:H1228-H1238 (2000)) and platelet-derived growth factor (PDGF) (Kishi, H. et al., J. Biochem., 128:719-722 (2000)). Many of these factors are implicated in the pathogenesis of cardiovascular disease.

[0004] Additional studies in the literature, some using the known ROCK inhibitors fasudil (Asano, T. et al., J. Pharmacol. Exp. Ther., 241:1033-1040 (1987)) or Y-27632 (Uehata, M. et al., Nature, 389:990-994 (1997)) further illustrate the link between ROCK and cardiovascular disease. For example, ROCK expression and activity have been shown to be elevated in spontaneously hypertensive rats, suggesting a link to the development of hypertension in these animals (Mukai, Y. et al., FASEB J., 15:1062-1064 (2001)). The ROCK inhibitor Y-27632 (Uehata, M. et al., Nature, ibid.) was shown to significantly decrease blood pressure in three rat models of hypertension, including the spontaneously hypertensive rat, renal hypertensive rat and deoxycortisone acetate salt hypertensive rat models, while having only a minor effect on blood pressure in control rats. This reinforces the link between ROCK and hypertension.

[0005] Other studies suggest a link between ROCK and atherosclerosis. For example, gene transfer of a dominant negative form of ROCK suppressed neointimal formation following balloon injury in porcine femoral arteries (Eto, Y. et al., Am. J. Physiol. Heart Circ. Physiol., 278:H1744-H1750 (2000)). In a similar model, ROCK inhibitor Y-27632 also inhibited neointimal formation in rats (Sawada, N. et al., Circulation, 101:2030-2033 (2000)). In a porcine model of IL-1 beta-induced coronary stenosis, long term treatment with the ROCK inhibitor fasudil was shown to progressively reduce coronary stenosis, as well as promote a regression of coronary constrictive remodeling (Shimokawa, H. et al., Cardiovasc. Res., 51:169-177 (2001)).

[0006] Additional investigations suggest that a ROCK inhibitor would be useful in treating other cardiovascular diseases. For example, in a rat stroke model, fasudil was shown to reduce both the infarct size and neurologic deficit (Toshima, Y., Stroke, 31:2245-2250 (2000)). The ROCK inhibitor Y-27632 was shown to improve ventricular hypertrophy, fibrosis and function in a model of congestive heart failure in Dahl salt-sensitive rats (Kobayashi, N. et al., Cardiovasc. Res., 55:757-767 (2002)).

[0007] Other animal or clinical studies have implicated ROCK in additional diseases including coronary vasospasm (Shimokawa, H. et al., Cardiovasc. Res., 43:1029-1039 (1999)), cerebral vasospasm (Sato, M. et al., Circ. Res., 87:195-200 (2000)), ischemia/reperfusion injury (Yada, T. et al., J. Am. Coll. Cardiol., 45:599-607 (2005)), pulmonary hypertension (Fukumoto, Y. et al., Heart, 91:391-392 (2005)), angina (Shimokawa, H. et al., J. Cardiovasc. Pharmacol., 39:319-327 (2002)), renal disease (Satoh, S. et al., Eur. J. Pharmacol., 455:169-174 (2002)) and erectile dysfunction (Gonzalez-Cadavid, N.F. et al., Endocrine, 23:167-176 (2004)).

[0008] In another study, it has been demonstrated that inhibition of the RhoA/ROCK signaling pathway allows formation of multiple competing lamellipodia that disrupt the productive migration of monocytes (Worthylake, R.A. et al., J. Biol. Chem., 278:13578-13584 (2003)). It has also been reported that small molecule inhibitors of Rho Kinase are capable of inhibiting MCP-1 mediated chemotaxis in vitro (Iijima, H., Bioorg. Med. Chem., 15:1022-1033 (2007)). Due to the dependence of immune cell migration upon the RhoA/ROCK signaling pathway one would anticipate inhibition of Rho Kinase should also provide benefit for diseases such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease.

[0009] The above studies provide evidence for a link between ROCK and cardiovascular diseases including hypertension, atherosclerosis, restenosis, stroke, heart failure, coronary vasospasm, cerebral vasospasm, ischemia/reperfusion injury, pulmonary hypertension and angina, as well as renal disease and erectile dysfunction. Given the demonstrated effect of ROCK on smooth muscle, ROCK inhibitors may also be useful in other diseases involving smooth muscle hyper-reactivity, including asthma and glaucoma (Shimokawa, H. et al., Arterioscler. Thromb. Vasc. Biol., 25:1767-1775 (2005)). Furthermore, Rho-kinase has been indicated as a drug target for the treatment of various other diseases, including airway inflammation and hyperresponsiveness (Henry, P.J. et al., Pulm. Pharmacol Ther., 18:67-74 (2005)), cancer (Rattan, R. et al., J. Neurosci. Res., 83:243-255 (2006); Lepley, D. et al., Cancer Res., 65:3788-3795 (2005)), fibrotic diseases (Jiang, C. et al., Int. J. Mol. Sci., 13:8293-8307 (2012); Zhou, L. et al., Am. J. Nephrol., 34:468-475 (2011)), as well as neurological disorders, such as spinal-cord injury, Alzheimer's disease, multiple sclerosis, stroke and neuropathic pain (Mueller, B.K. et al., Nat. Rev. Drug Disc., 4:387-398 (2005); Sun, X. et al., J. Neuroimmunol., 180:126-134 (2006)).

[0010] There remains an unmet medical need for new drugs to treat cardiovascular disease. In the 2012 update of Heart Disease and Stroke Statistics from the American Heart Association (Circulation, 125:e2-e220 (2012)), it was reported that cardiovascular disease accounted for 32.8% of all deaths in the U.S., with coronary heart disease accounting for ~1 in 6 deaths overall in the U.S.. Contributing to these numbers, it was found that ∼33.5% of the adult U.S. population was hypertensive, and it was estimated that in 2010 ~6.6 million U.S. adults would have heart failure. Therefore, despite the number of medications available to treat cardiovascular diseases (CVD), including diuretics, beta blockers, angiotensin converting enzyme inhibitors, angiotensin blockers and calcium channel blockers, CVD remains poorly controlled or resistant to current medication for many patients.

[0011] Although there are many reports of ROCK inhibitors under investigation (see, for example, US 2012/0122842 A1, US 2010/0041645 A1, US 2008/0161297 A1, and Hu, E. et al., Exp. Opin. Ther. Targets, 9:715-736 (2005), and WO2014/113620, WO 2014/134388, WO 2014/134391, WO2015/002915, WO2015/002926, WO2016/010950, WO2016/028971, WO2016/112236, and WO2016/144936, of which the later nine references are assigned to the present applicant), fasudil is the only marketed ROCK inhibitor at this time. An i.v. formulation was approved in Japan for treatment of cerebral vasospasm. There remains a need for new therapeutics, including ROCK inhibitors, for the treatment of cardiovascular diseases, cancer, neurological diseases, renal diseases, fibrotic diseases, bronchial asthma, erectile dysfunction, and glaucoma.

SUMMARY OF THE INVENTION

[0012] The present invention provides novel spiroheptane salicylamides, their analogues, including stereoisomers, enantiomers, diastereoisomers, tautomers, pharmaceutically-acceptable salts, or solvates thereof, which are useful as selective inhibitors of Rho kinases.

[0013] The present invention also provides processes and intermediates for making the compounds of the present invention.

[0014] The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, enantiomers, diastereoisomers, tautomers, pharmaceutically-acceptable salts, or solvates thereof.

[0015] The compounds of the invention may be used in the treatment and/or prophylaxis of conditions associated with aberrant ROCK activity.

[0016] The compounds of the present invention may be used in therapy.

[0017] The compounds of the present invention may be used for the manufacture of a medicament for the treatment and/or prophylaxis of a condition associated with aberrant ROCK activity.

[0018] In another aspect, the present invention is directed to a method of treating a cardiovascular or related disease which method comprises administering to a patient in need of such treatment a compound of the present invention as described above. Examples of such diseases that may be treated include, for example, hypertension, atherosclerosis, restenosis, stroke, heart failure, renal failure, coronary artery disease, peripheral artery disease, coronary vasospasm, cerebral vasospasm, ischemia/reperfusion injury, pulmonary hypertension, angina, erectile dysfunction and renal disease.

[0019] In another aspect, the present invention is directed to a method of treating diseases involving smooth muscle hyper reactivity including asthma, erectile dysfunction and glaucoma, which method comprises administering to a patient in need of such treatment a compound of the present invention as described above.

[0020] In another aspect, the present invention is directed to a method of treating diseases mediated at least partially by Rho kinase including fibrotic diseases, oncology, spinal-cord injury, Alzheimer's disease, multiple sclerosis, stroke, neuropathic pain, rheumatoid arthritis, psoriasis and inflammatory bowel disease, which method comprises administering to a patient in need of such treatment a compound of the present invention as described above.

[0021] In yet additional aspects, the present invention is directed at pharmaceutical compositions comprising the above-mentioned compounds, processes for preparing the above-mentioned compounds and intermediates used in these processes.

[0022] The compounds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more, preferably one to two other agent(s).

[0023] These and other features of the invention will be set forth in expanded form as the disclosure continues.

DETAILED DESCRIPTION OF THE INVENTION

I. COMPOUNDS OF THE INVENTION

[0024] In one aspect, the present invention provides, inter alia, compounds of Formula (I):

or stereoisomers, enantiomers, diastereoisomers, tautomers, pharmaceutically-acceptable salts, sovates, or prodrugs thereof, wherein:

Ring A is selected from phenyl or 6-membered heteroaryl comprising carbon atoms and 1-2 nitrogen atoms;

R¹ is selected from C_1-4 alkyl, NR⁵R⁵, OR⁵, -(CR⁴R⁴)_nC_3-10 carbocycle and -(CR⁴R⁴)_n-4- to 15-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_p; wherein said alkyl, carbocycle, and heterocycle are substituted with 1-4 R⁷;

R² is independently selected from H and C_1-5 alkyl optionally substituted with halogen, C_1-4 alkoxy, -OH, CN, -CO₂H, -CO₂(C_1-4 alkyl), -CO(C_1-4 alkyl), -CONH₂, -CONH(C_1-4 alkyl), and -CON(C_1-4 alkyl)₂; wherein said alkyl and alkoxy are substituted with 0-4 R⁹;

R³, at each occurrence, is independently selected from halogen, C_1-6 alkyl, C_1-4 alkoxy, C_1-4 alkylthio, C_1-4 haloalkyl, -CH₂OH, -OCH₂F, -OCHF₂, -OCF₃, CN, -NH₂, -NH(C_1-4 alkyl), -N(C_1-4 alkyl)₂, -CO₂H, -CH₂CO₂H, -CO₂(C_1-4 alkyl), -CO(C_1-4 alkyl), -CH₂NH₂, -CONH₂, -CONH(C_1-4 alkyl), -CON(C_1-4 alkyl)₂, -OCH₂CO₂H, -NHCO(C_1-4 alkyl), -NHCO₂(C_1-4 alkyl), -NHSO₂(C_1-4 alkyl), -SO₂NH₂, -C(=NH)NH₂, a carbocycle, and a heterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl, carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁴, at each occurrence, is independently selected from H, OH, NH₂, CH₂NH₂, C_1-4 haloalkyl, OCH₂F, OCHF₂, OCF₃, -NH(C_1-4 alkyl), -N(C_1-4 alkyl)₂, C_1-4 alkoxy, CH₂OH, CH₂O(C_1-4 alkyl), CH₂CO₂H, CH₂CO₂(C_1-4 alkyl), C_1-4 alkyl, a carbocycle, and a heterocycle, wherein said alkyl, alkoxy, haloalkyl, carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁵, at each occurrence, is independently selected from H, C_1-4 alkyl, -(CR⁶R⁶)_n-C_3-10 carbocycle and -(CR⁶R⁶)_n-4- to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_p, wherein said alkyl, carbocycle and heterocycle are substituted with 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom to which they are attached to form a 4- to 15-membered substituted with 1-4 R⁷;

R⁶, at each occurrence, is independently selected from H, C_1-4 alkyl, CH₂NH₂, C_1-4 haloalkyl, C_1-4 alkoxy, CH₂OH, CH₂O(C_1-4 alkyl), CH₂CO₂H, CH₂CO₂(C_1-4 alkyl), a carbocycle, and a heterocycle, wherein said alkyl, alkoxy, haloalkyl, carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁷, at each occurrence, is independently selected from H, =O, NO₂, halogen, C_1-7 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_1-4 alkoxy, CN, OH, CHF₂, CF3, -(CH₂)_n-CO₂H, -(CH₂)_n-CO₂(C_1-4 alkyl), -(CH₂)_n-NR⁸R⁸, -NHCOH, -NHCO(C_1-4 alkyl), -NHCOCF₃, -NHCO₂(C_1-4 alkyl), -NHCO₂(CH₂)₂O(C_1-4 alkyl), -NHCO₂(CH₂)₃O(C_1-4 alkyl), -NHCO₂(CH₂)₂OH, -NHCO₂(CH₂)₂NH₂, -NHCO₂(CH₂)₂N(C_1-4 alkyl)₂, -NHCO₂CH₂CO₂H, -CH₂NHCO₂(C_1-4 alkyl), -NHC(O)NR⁸R⁸, -NHSO₂(C_1-4 alkyl), -S(O)_p(C_1-4 alkyl), -SO₂NH₂, -SO₂NH(C_1-4 alkyl), -SO₂N(C_1-4 alkyl)₂, -SO₂NH(CH₂)₂OH, -SO₂NH(CH₂)₂O(C_1-4 alkyl), -(CH₂)_n-CONR⁸R⁸, -O(CH₂)_n-carbocycle, -O(CH₂)_n-heterocycle, -NHCO-carbocyc le, -NHCO-heterocycle, -(CH₂)_n-carbocycle, and -(CH₂)_n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_p, wherein said alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C_1-6 alkyl, C_2-4 alkenyl, C2-4 alkynyl, -(CH₂)n-C(O)C_1-4alkyl, -(CH₂)_n-C(O)carbocycle, -(CH₂)_n-C(O)heterocycle, -(CH ₂)_n -C(O)NR^aR^a, -(CH₂)_n-NR^aC(O) C_1-4alkyl, -(CH₂)_n-C(O)OC_1-4alkyl, -(CH₂)n-C(O)C_1-4alkyl, -(CH₂)_n-C(O)O-carbocycle, -( CH₂)_n-C(O)O-heterocycle, -(CH₂)_n-SO₂alkyl, -(CH2)n SO₂carbocycle, -(CH₂)_n-SO₂heterocycle, -(CH₂)_n-SO₂NR^aR^a, -(CH₂)_n-carbocycle, and -(CH₂)_n-heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R⁹;

alternatively, R⁸ and R⁸ are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocycle substituted with 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, =O, CN, NO₂, CHF₂, CF₃, C_1-4 alkyl, C_1-4 alkoxy, CH₂OH, CO(C_1-4 alkyl), CO₂H, CO₂(C_1-4 alkyl), -(CHR¹⁰)_nNR^aR^a, -(CHR¹⁰)_nCONR^aR^a, -(CHR¹⁰)_nNR^aCO(C_1-4 alkyl), -O(CHR¹⁰)_ncarbocycle, -O(CHR¹⁰)_nheterocycle, -O(CHR¹⁰)_nNR^aR^a, and -(CR¹⁰R¹⁰)_n-4- to 10-membered heterocycle, wherein said alkyl, alkoxy, carbocycle, and heterocycle are substituted with 0-4 R^b;

R¹⁰, at each occurrence, is independently selected from H and C_1-4 alkyl;

R¹¹ is independently selected from H and C_1-3 alkyl optionally substituted with halogen, C_1-4 alkoxy, -OH, CN, -CO₂H, -CO₂(C_1-4 alkyl), -CO(C_1-4 alkyl), -CONH₂, -CONH(C_1-4 alkyl), and -CON(C_1-4 alkyl)₂;

R¹² and R¹³ are independently selected from H, OH, -OC_1-3 alkyl substituted with 0-4 R^d, C_1-3 alkyl with substituted with 0-4 R^d;

R^a, at each occurrence, is independently selected from H, C_1-4 alkyl, -(CH₂)_nOH, CO(C_1-4 alkyl), COCF₃, CO₂(C_1-4 alkyl), -CONH₂, -CONH-C_1-4 alkylene-CO₂(C_1-4 alkyl), C_1-4 alkylene-CO₂(C_1-4 alkyl), R^c, CO₂R^c, and CONHR^c; alternatively, R^a and R^a are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocycle, wherein said alkyl, alkylene, and heterocycle are substitutedwith 0-4 R^b;

R^b, at each occurrence, is independently selected from =O, OH, halogen, C_1-4 alkyl, C_1-4 alkoxy, OCF₃, OC(O)C_1-4 alkyl, NH₂, NO₂, N(C_1-4 alkyl)₂, CO(C_1-4 alkyl), CO(C_1-4 haloalkyl), CO₂(C_1-4 alkyl), CONH₂, -CONH(C_1-4 alkyl), -CON(C_1-4 alkyl)₂, -CONH-C_1-4 alkylene-O(C_1-4 alkyl), -CONH-C_1-4 alkylene-N(C_1-4 alkyl)₂, -CONH-C_1-4 alkylene-N (C_1-4 alkyl)₂, -C_1-4 alkylene-O-P(O)(OH)₂, -NHCO₂(C_1-4 alkyl), -R^c, COR^c, CO₂R^c, and CONHR^c, wherein said alkyl and alkoxy are substituted with R^d;

R^c, at each occurrence, is independently selected from -(CH₂)_n-C_3-6 cycloalkyl, -(CH₂)_n-phenyl, and -(CH₂)_n-5- to 6-membered heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of: N, NH, N(C_1-4 alkyl), O, and S(O)_p; wherein each ring moiety is substituted with 0-2 R^d;

R^d, at each occurrence, is independently selected from =O, halogen, -OH, C_1-4 alkyl, NH₂, NH(C_1-4 alkyl), N(C_1-4 alkyl)₂, C_1-4 alkoxy, and -NHCO(C_1-4 alkyl);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4; and

p, at each occurrence, is independently selected from 0, 1, and 2.

[0025] In another aspect, the present invention provides compounds of Formula (Ia):